Purpose: This study aims to assess and compare the effectiveness of perineural dexamethasone (DEX) and perineural dexmedetomidine (DEM) as adjuvant in popliteal sciatic and saphenous nerve blocks, focusing on the duration of analgesia and side effects following major foot and ankle surgeries. Patients and Methods: Ninety patients scheduled for major foot and ankle surgeries under general anesthesia, who received popliteal sciatic and saphenous nerve blocks, were randomly assigned to one of three groups: (1) control group receiving 0.375% ropivacaine; (2) DEX group receiving 0.375% ropivacaine combined with 10 mg perineural dexamethasone; (3) DEM group receiving 0.375% ropivacaine combined with 0.75 mu g/kg perineural dexmedetomidine. The primary outcome measured was the duration of analgesia, defined as the time from the administration of the nerve block to the onset of the first pain sensation in the surgical area. Secondary outcomes included opioid consumption within the first 48 hours post-surgery and the incidence of side effects such as hypotension and bradycardia. (Clinical trial registration number: ChiCTR2100048127). Results: The time until the first perception of pain was significantly extended in the DEX group (28.0 (3.3) hours) compared to the DEM group (24.1 (1.3) hours) and the control group (17.5 (3.5) hours, P<0.001). Additionally, opioid consumption within the first 24 hours was markedly reduced in both the DEX and DEM groups compared to the control group (P<0.001). However, opioid usage between 0 to 48 hours post-surgery showed no significant differences among the three groups. The DEM group experienced a higher incidence of hypotension and bradycardia compared to both the DEX and control group (P<0.001). Conclusion: Both 10 mg dexamethasone and 0.75 <mu>g/kg dexmedetomidine effectively prolonged analgesia in patients undergoing major foot and ankle surgery with a popliteal sciatic and saphenous nerve block. However, dexamethasone (10 mg) provided a significantly longer duration of analgesia compared to dexmedetomidine (0.75 mu g/kg).